Introduction: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate shortening of the extremities, predominantly affecting middle and distal limb segments. It results from loss-of-function mutations affecting the C-type natriuretic peptide (CNP) receptor (NPR-B), a transmembrane guanylyl cyclase receptor encoded by the NPR2 gene. Resistance to growth hormone (GH) action has been suggested in AMDM. We previously reported an improvement in height velocity over 2 years of high-dose GH in two siblings with AMDM. We now present their final height outcomes.
Patients and Methods: Two siblings (Pt-A and Pt-B; consanguineous parents) presented in early childhood with severe disproportionate short stature and radiological signs of AMDM. Mother's height -0.65SDS; Father's height -2.08SDS. Subsequent genetic testing identified a novel homozygous NPR2 variant (c.2548_2551delGAGA; p.[Glu850fs]) in both siblings. GH provocation testing (Glucagon) showed relatively high GH levels throughout (Pt-A 7.6 years, male, height -5.6SDS, peak/nadir GH21.6/4.8mcg/L; Pt-B 5.7 years, female, height -4.5SDS, peak/nadir GH12/1.3mcg/L). Serum IGF1 levels (60 and 37mcg/L) were >2SD below age/sex specific mean value. In view of results suggesting relative resistance to GH, high-dose GH (70-75mcg/kg/d subcut.) was started. Pre-GH height velocities were 3.7 (Pt-A) and 4.5 (Pt-B) cm/year. GH dose was adjusted to sustain serum IGF1 levels towards the upper end of reference range for age. Annualized height velocities for first, second and third year on GH treatment were 7.0, 5.4 and 4.7cm/yr (Pt-A) and 9.4, 8.0 and 5.9cm/yr (Pt-B). Puberty onset was at 12.8(Pt-A) and 11.9(Pt-B) yrs. Height gain during puberty was 10.6(Pt-A) and 5.9(Pt-B) cm. Final height after 8.5 yrs of GH treatment was 130.5cm (-6.57SDS, Pt-A) and 134 cm (-4.58SDS, Pt-B).
Conclusions: To the best of our knowledge, this is the first report of final height in patients with AMDM after long-term GH treatment. Our patients with AMDM had GH/IGF1 profiles consistent with a degree of intrinsic GH resistance. GH treatment with doses 3-4 fold higher than conventional GH replacement increased their serum IGF1 levels to upper limit of age- and sex-related reference range, which was associated with increase to greatest height SDS (Pt-A -4.33SDS; Pt-B -2.76SDS) close to onset of puberty. Although this early improvement in height SDS enhanced their quality of lives, this was not sustained through puberty and probably failed to translate into improved final height.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology